Remedy for pemphigoid

ABSTRACT

An agent for treatment of pemphigoid is provided. For use as an agent for treatment of pemphigoid, IFN-γ is administered in a dose of 2,000,000 JRU once daily for 7 days by intravenous drip infusion. Depending on symptoms, side effects and age of a patient, the dose can be change, or the dosage can changed to intravenous drip infusion given once in several days. IFN-γ is fast-acting against pemphigoid, involves few side effects, and is considered to be effective. The mechanism of action is presumed to be that IFN-γ suppresses the chemotaxis and function of eosinophils which are considered to be directly involved in the occurrence of pemphigoid.

TECHNICAL FIELD

This invention relates to an agent for treatment of pemphigoid,containing interferon gamma (IFN-γ) as an active ingredient.

BACKGROUND ART

Pemphigoid is a skin disease classified as a type of acquired bullousdermatosis among bullous dermatoses. It is an autoimmune diseaseclassified into bullous pemphigoid (including nodular pemphigoid),cicatricial pemphigoid (benign mucosal pemphigoid), herpes gestationis,and juvenile pemphigoid. Cicatricial pemphigoid (benign mucosalpemphigoid) is further subclassified into anti-BP180 type cicatricialpemphigoid, anti-laminin 5 type cicatricial pemphigoid, and ocularcicatricial pemphigoid.

Of these diseases, bullous pemphigoid (BP) is one of representativeautoimmune bullous dermatoses in the field of dermatology. Itscharacteristic clinical symptoms start with edematous erythemas. Then,tense blister, large and small, develop in erythematous plaques, andonly blister appear occasionally. These symptoms occur mainly in theextremities and trunk with a high incidence, rupture and form erosions.Erosions, if systemically generated, may cause bacterial infection, andlosses of water and protein in the body. Thus, edemas may developsystemically, or electrolyte abnormality in the blood and dehydrationmay occur, resulting in a worsened generalized condition. Pruritus isfrequently noted as a subjective symptom. In terms of age, BP occursmost frequently in elderly people at 70 years of age or higher, but mayrarely occur in children and young persons. Histopathological findingsinclude subepidermal blisters, and inflammatory cell infiltrationspredominantly of the eosinophilic origin. The direct immunofluorescencetechnique shows deposition of IgG and C3 in the basement membrane zone.Visceral malignant tumor may be occasionally involved as a complication,partly because BP occurs most frequently in the elderly.

In the treatment of pemphigoid typified by BP, external use ofcorticosteroids has so far been performed for erythema as a dermalsymptom, and external use of Eksalb® or zinc oxide ointment (unguentumsimplex) has been performed for erosion. Since external use of suchdrugs alone has proved insufficient in efficacy, however, oraladministration of tetracycline antibiotics (Minomycin®, Achromycin®,nicotinamide, and corticosteroids has been implemented for systemicadministration. If these treatments are still ineffective, systemicadministration of immunosuppressants or plasmapheresis has been carriedout. For pruritus, antihistaminics or antiallergic drugs have beenadministered as symptomatic therapies.

IFN-γ, on the other hand, has been demonstrated to have variousbiological actions, since it was discovered as a virus proliferationinhibiting factor produced by cells. Studies aimed at its clinicalapplications based on these actions have been conducted to show itseffectiveness against atopic dermatitis, herpesvirus infection, andcutaneous T cell lymphoma among skin diseases. However, the results ofinvestigation of the effectiveness of IFN-γ against pemphigoid have notbeen reported. Nor have there been any reports of cases of its use inthe clinical setting.

DISCLOSURE OF THE INVENTION

In treating pemphigoid, it requires a follow-up care for a long termeven after it is alleviated and nearly healed, because this disease isan autoimmune disease. Usually, its treatment begins with the oraladministration of tetracycline antibiotics and nicotinamide whosesystemic burden is light. However, the oral administration of thesedrugs alone is not sufficiently effective in many patients, and thesystemic administration of corticosteroids is often concomitantly used.In the systemic administration of corticosteroids, large doses areadministered at the start of treatment, and often produce an excellenteffect. However, hospital stay for about 2 months is required until thedose is decreased to a safety dose permitting treatment at theoutpatient clinic. If the corticosteroids prove ineffective, systemicadministration of immunosuppressants or plasmapheresis may be usedconcomitantly.

In the elderly, such treatments performed for long periods are prone tocause complications, such as hypertension, diabetes, osteoporosis,interstitial pneumonia, and bacterial infection. Once such complicationsoccur, therapy for their symptoms may be needed to lengthen the periodof hospitalization to 3 to 4 months. Furthermore, the patients may beextremely debilitated, and die of complications. Alternatively, whilethe doses of the administered drugs are decreased, eruptions may beaggravated. Increasing the doses again may postpone discharge from thehospital, posing difficulty with treatment.

Hence, treatment with a pharmaceutical is desired, the pharmaceuticalwhich, when used alone, is effective, is fast-acting and involves fewside effects, whose action is persistent for a long term, and whichenables a corticosteroid or an immunosuppressant, if used concomitantly,to be promptly decreased in dose, even if recurrence of pemphigoid isnoted during treatment with the pharmaceutical. In the presence of sucha pharmaceutical, the patient would be able to leave the hospital andreturn to society early. In the event of recurrence, rehospitalizationfor a short term would be able to achieve successful treatment. Againstthe background of these circumstances, the present invention has, as anobject, the provision of a pharmaceutical which can solve theabove-described problems in the therapy of pemphigoid.

MEANS FOR SOLVING THE PROBLEMS

The inventor has clarified that IFN-γ shows a marked therapeutic effecton pemphigoid, thus accomplishing the present invention. That is, thepresent invention provides an agent for treatment of pemphigoid, whichcontains IFN-γ as an active ingredient. IFN-γ is fast-acting againstpemphigoid, involves few side effects, and proves effective. Themechanism of action of IFN-γ is presumed to be that IFN-γ suppresses thechemotaxis and function of eosinophils which are considered to bedirectly involved in the onset of pemphigoid.

Pemphigoid herein refers to an autoimmune disease, including bullouspemphigoid (BP), nodular pemphigoid, cicatricial pemphigoid, juvenilepemphigoid, and other pemphigoid. Particularly, bullous pemphigoid,cicatricial pemphigoid, and nodular pemphigoid, typically, bullouspemphigoid, can be expected to be successfully treated with the agentfor treatment according to the present invention. Moreover, treatment ofpemphigoid is taken to have meanings, including the alleviation ofsymptoms of pemphigoid by administration of IFN-γ, the prevention ofreaggravation of alleviated symptoms, and the suppression of incidenceof symptoms in patients suspected of having initial symptoms ofpemphigoid.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 a to 1 c are clinical course photographs (right thigh) of Case1, FIG. 1 a showing a clinical image before treatment with IFN-γ, FIG. 1b showing a clinical image after 2 days of IFN-γ treatment, and FIG. 1 cshowing a clinical image after completion of 7V.

FIGS. 2 a and 2 b are clinical course photographs of Case 2, FIG. 2 ashowing a clinical image before treatment with IFN-γ, and FIG. 2 bshowing a clinical image after completion of 7V.

FIGS. 3 a and 3 b are clinical course photographs (chest) of Case 3,FIG. 3 a showing a clinical image before treatment with IFN-γ, and FIG.2 b showing a clinical image after treatment.

FIGS. 4 a to 4 c are clinical course photographs (abdomen) of Case 6,FIG. 4 a showing a clinical image before treatment with IFN-γ, FIG. 4 bshowing a clinical image after 3 days of treatment with IFN-γ, and FIG.4 c showing a clinical image after completion of 7V.

FIGS. 5 a and 5 b are clinical course photographs (back) of Case 6, FIG.5 a showing a clinical image before treatment with IFN-γ, and FIG. 5 bshowing a clinical image after completion of 7V.

MODES FOR CARRYING OUT THE INVENTION

IFN-γ used in the present invention may be that of the natural orrecombinant gene type, such as IFN-γ1a (interferon gamma-1a), IFN-γ1b(interferon gamma-1b), and IFN-γn1 (interferon gamma-n1). However, IFN-γof the recombinant gene type is preferred as a stable source of supply.For example, Biogamma®, which is an IFN-γ preparation marketed byDaiichi Suntory Pharma as an agent for treatment of mycosis fungoides,can be used directly. Unless the effectiveness of the present inventionis lost, an IFN-γ mutant resulting from the deletion, insertion andsubstitution of a constituent amino acid effected in the above IFN-γ canbe used, instead of this IFN-γ, with the IFN-γ mutant being adjustedsuch that its clinical use can be made. Examples of such an IFN-γ mutantare the IFN-γ in which 4 amino acids (Cys-Tyr-Cys-Gin) at the N-terminalhave been deleted (Japanese Patent Publication No. 1995-45516), that inwhich an amino acid at the C-terminal has been deleted by processing(for example, a mutant described in Japanese Patent ApplicationLaid-Open No. 1985-84298, prepared by deletion of the C-terminal 11amino acids), and that in which the 9th amino acid has been convertedfrom Lys to Gln (for example, Japanese Patent Publication No.1995-45515).

The agent for treatment according to the present invention containsIFN-γ, preferably, as an intravenous preparation for drip infusion, fortreatment of pemphigoid. The agent for treatment of pemphigoid accordingto the present invention can be administered, for example, such that200,000. to 4,000,000 JRU of IFN-γ, once or several times daily, isadministered every day or every suitable days according to symptoms,with the symptoms being observed. The dose, the administration interval,and the administration frequency can be changed, as appropriate,according to symptoms, side effects, and the patient's age.

An example of the preferred mode is the intravenous drip infusion of2,000,000 JRU, once daily, for 7 consecutive days. After alleviation ofsymptoms, this dose can be administered at intervals, i.e., every 2 to 3days, or once in 1 to 2 weeks. If a side effect due to this treatmentoccurs, the dosage can be changed to an intravenous drip infusion oncein several days according to its symptoms. To suppress fever, one ofside effects, an analgesic antipyretic drug can be used in combination.Furthermore, systemic administration of pharmaceuticals which have beenused in the treatment of pemphigoid, such as corticosteroids, and theconcomitant use of antihistaminics and antiallergics as symptomatictherapies are also possible. As steroid drugs, for example,prednisolone, methylprednisolone, betamethasone, and dexamethasone canbe used. As antiallergics, ketotifen fumarate, olopatadinehydrochloride, cetirizine hydrochloride, ebastine, and fexofenadinehydrochloride can be used. As antihistaminics, homochlorcyclizinehydrochloride, chlorpheniramine maleate, mequitazine, clemastinefumarate, and cyproheptadine hydrochloride can be used. However, thesedrugs are not restrictive, and the steroid drugs, antiallergics, andantihistaminics usually used in the field of dermatology can all beused. These drugs may be incorporated, together with IFN-γ, into thepharmaceutical preparation of the present invention, or may be usedconcomitantly as separate drugs.

The pharmaceutical preparation of the present invention may containcarriers, adjuvants, and additives, which are customarily used for theproduction of pharmaceuticals, in addition to IFN-γ. For example, IFN-γcan be prepared into pharmaceutical preparations, such as intravenousinjections, by publicly known pharmaceutical manufacturing methods usingthose agents, including tonicity agents, such as sodium chloride andpotassium chloride; buffering agents, such as sodium hydrogenphosphate,and sodium dihydrogenphosphate; stabilizers, such as sodium edetate;antiseptics, such as ethylparaben, butylparaben, and benzalkoniumchloride; and pH adjustors, such as sodium hydroxide and dilutehydrochloric acid. IFN-γ preparations can be produced, for example, byadding suitable stabilizers and buffering agents to a purified IFN-γstock solution, and lyophilizing the mixture.

The effect of treating pemphigoid by the agent for treatment, whichcontains IFN-γ, according to the present invention is evaluated by theefficacy evaluation method performed in daily medical care, which usesamelioration of dermal symptoms, etc. In the case of bullous pemphigoid,for example, three symptoms in the patient, i.e., erythemas, blister anderosions, are used as indicators, and the severity of these symptoms,before, during and after treatment with the therapeutic agent of thepresent invention, is evaluated on a scale of 5 grades, whereby theefficacy of the agent for treatment according to the present inventioncan be evaluated. For example, erythemas, blister and erosions areevaluated by the 5-grade system described below. If a favorable changeoccurs in at least one of these indicators, it is determined that thesymptoms of the patient with pemphigoid has been alleviated.

1) Erythemas

-   -   0: No erythemas. Almost all of lesions are pigmentations.    -   1: Erythemas account for less than ⅓ of all lesions. The        remainder are pigmentations.    -   2: Erythemas account for ⅓ to ⅔ of all lesions. The remainder        are pigmentations.    -   3: Unchanged.    -   4: Erythemas expand and newly develop.        2) Blister    -   0: No bullae.    -   1: Less than ⅓ of the number of blister present at admission to        hospital.    -   2: ⅓ to ⅔ of the number of blister present at admission to        hospital.    -   3: No change in the number of blister.    -   4: Blister newly develop.        3) Erosions    -   0: No erosions. Nearly all lesions are epithelialized.    -   1: Erosions are less than ⅓ of erosions present at admission to        hospital. The remainder are epithelialized.    -   2: Erosions are ⅓ to ⅔ of erosions present at admission to        hospital. The remainder are epithelialized.    -   3: No change in the area of erosions.    -   4: Erosions tend to expand.        [Actions]

The mechanism of action of IFN-γ, namely, how IFN-γ works effectively inthe treatment of pemphigoid, has not yet been accurately elucidated,like the mechanism of onset of pemphigoid which has remained stillunknown. Pemphigoid is an autoimmune disease, and involves peripheralblood eosinophilia and marked eosinophilic infiltration into tissues.The inventor and others previously conducted immunohistological studiesand electron microscopic morphological studies of eosinophilsinfiltrating into tissues of patients with pemphigoid, and reported thateosinophils were involved in the generation of BP¹⁾²⁾. They alsoclarified that in the peripheral blood eosinophils of patients withpemphigoid, density heterogeneity of eosinophils existed, and hypodenseactive eosinophils significantly increased³⁾, and that ECP concentrationin a BP bullous liquid was markedly high⁴⁾. BP is an autoimmune disease,and it is speculated that pemphigoid can be treated by suppressing theinfiltration and function of eosinophils which may be fully involved inthe occurrence of BP, as described above.

There are many factors which differentiate, induce and activateeosinophils. It has been elucidated, in particular, that cytokines, suchas IL-3, IL-5 and GM-CSF, are mainly involved as factors acting onhematopoietic stem cells of the bone marrow to the peripheral blood.Normally, helper T cells of peripheral blood T cells are classified intoTh1 cells and Th2 cells by the type of cytokines produced by the helperT cells, and the above-mentioned IL-3, IL-5 and GM-CSF are produced byTh2 cells. In the normal state, there is a balance, between these twotypes of cells, such that Th2 cells are suppressed via IFN-γ produced byTh1 cells, and Th1 cells are suppressed by IL-10 produced by Th2 cells.

Since Th2 cells are dominant, IL-3, IL-5 and GM-CSF may partake ineosinophilic leukocytosis and eosinophilic infiltration concerned withthe pathogenesis of pemphigoid. Thus, it is assumed that theadministration of IFN-γ will suppress the function of Th2 cells tosuppress the production of IL-3, IL-5 and GM-CSF, thereby suppressingthe differentiation, induction and activation of eosinophils, thuseventually leading to the alleviation of symptoms of pemphigoid.

EXAMPLES

Cases in which IFN-γ produced an excellent response in BP patientsintractable to various therapies will be explained by way of Examples.

[Clinical Case 1] Example (1) of Treatment with IFN-γ in BP Patient

-   Subject: A 58-year-old male.-   Chief complaints: Systemic edematous erythemas, blister, erosions.-   Family history: Nothing of note.-   Past history: Schizophrenia and epilepsy since 1992.-   Present illness and course: Tense blister frequently occurred at the    upper extremities and back since February 2001. Upon scrutiny at    Kurume University Hospital, a diagnosis of BP was made. The oral    administration of Achromycin® and nicotinamide was begun, but    because of aggravation, concomitant use of prednisolone, 30 mg p.o.,    was initiated. The symptoms were alleviated transiently, but when    the dose of prednisolone was decreased to 15 mg, the symptoms were    recrudescent. Thus, the dose of prednisolone was increased to 30 mg,    but blister developed newly, necessitating admission to the hospital    in January 2002. After admission, plasmapheresis was performed a    total of 13 times, and the steroid administered orally was changed    from 3 mg betamethasone to 50 mg prednisolone. As the symptoms were    alleviated, the dose of prednisolone was decreased from 40 mg to 20    mg to 15 mg, and the patient was discharged from the hospital in    April 2002. Then, the course of the patient's condition was followed    up at the outpatient department over 15 mg prednisolone, 100 mg    minocycline, and 900 mg nicotinamide. One month after discharge from    the hospital, large and small bullae systemically occurred again at    multiple sites, and thus the patient was admitted again to the    hospital in May 2002. After admission, many bullae and erosions were    observed systemically, but the doses of prednisolone, minocycline    and nicotinamide were not increased. Instead, the administration of    IFN-γ, 2,000,000 JRU (1V) once daily for consecutive days by i.v.    drip infusion, was begun on May 24. However, an epileptic attack    occurred on May 26, necessitating discontinuation of IFN-γ    treatment. Because of the past history, IFN-γ treatment on alternate    days was cautiously resumed on May 29, and 7V was completed by    June 4. Since an excellent response was obtained, 1V was given once    in 3 to 4 days thereafter. In August, intravenous drip infusion was    performed once weekly without recurrence. Currently, the patient's    course is satisfactory through drip infusion performed once biweekly    at the outpatient department. In regard to oral administration,    minocycline and nicotinamide were discontinued, and prednisolone is    continued only in a dose of 5 mg, but prednisolone is to be    discontinued sometime. Epilepsy was observed only once, and not seen    thereafter. Thus, its relation with IFN-γ was negated. Fever after    administration of IFN-γ was observed in the 38° C. to the 39° C.    range until the fourth administration, but thereafter changed to    slight fever in the 37° C. range. Currently, no antipyretic is used.

Before IFN-γ treatment (May 23), blister and erosions developedsystemically at multiple sites (FIG. 1 a). After 2 days of treatment(May 26), the symptoms were considerably relieved (FIG. 1 b). Atcompletion of 7V (June 5), no blister newly occurred, and furtheralleviation was observed (FIG. 1 c). At present, all lesions arepigmentations, and none of erythemas, blister and erosions are seen. Theevaluations were 2 (May 26)→1 (June 5)→0 (August 22) for erythemas, 1(May 26)→0 (June 5)→0 (August 22) for blister, and 2 (May 26)→1 (June5)→0 (August 22) for erosions, as shown in Table 1.

The peripheral blood eosinophil count decreased as follows: 1190 (May23)→1246 (May 27)→602 (June 4)→356 (September 4). The blood IL-3, IL-4,IL-5 and GM-CSF levels all showed low values before and after IFN-γtreatment. TABLE 1 Day of examination May 26 June 5 August 22 Erythemas2 1 0 Blister 1 0 0 Erosions 2 1 0

[Clinical Case 2] Example (2) of Treatment with IFN-γ in BP Patient

-   Subject: A 74-year-old male.-   Chief complaints: Edematous erythemas and blister of the extremities    and trunk.-   Family history: Nothing of note.-   Past history: Cerebral infarction in 1992.-   Present illness and course: Erythemas accompanied by pruritus    occurred frequently in April 2002. External application of a    corticosteroid, and the oral administration of celestamine were    prescribed by a local doctor, but erythemas with blister began to    appear. Thus, the patient was referred to Kurume University    Hospital. Upon close examination, a diagnosis of BP was made, and    the oral administration of 300 mg roxithromycin, 1,500 mg    nicotinamide, and 20 mg prednisolone was started on May 8. Since the    symptoms were not alleviated, however, the patient was admitted to    the hospital on May 17. The oral administration of these drugs was    continued in the same doses, but new occurrence of blister was    observed. Thus, the administration of IFN-γ, 2,000,000 JRU (1V) once    daily by i.v. drip infusion, was begun on June 15. Following this    treatment for 7 consecutive days, an excellent response was    obtained, and then IFN-γ treatment was changed to i.v. drip infusion    performed once in 3 days. The dose of prednisolone was also    decreased to 12.5 mg, beginning on June 22, and further decreased to    10 mg from July 8. Since no recurrence was observed thereafter, the    patient was given IFN-γ once weekly, and discharged from the    hospital on August 7. Currently, the dose of prednisolone is 5 mg,    and IFN-γ is administered once biweekly by drip infusion, with no    recurrence seen.

Before IFN-γ treatment (June 14), erythemas, blister and erosionsdeveloped systemically at multiple sites (FIG. 2 a). At completion of 7V(June 21), all the blister disappeared, and nearly all of the erosionswere epithelialized (FIG. 2 b). The evaluations were 1 (June 17)→0 (June21) for erythemas, 1 (June 17)→0 (June 21) for blister, and 1 (June17)→0 (June 21) for erosions, as shown in Table 2. Still now, norecurrence of eruptions is noted.

The peripheral blood eosinophil count decreased as follows: 2619 (June13)→1136 (June 18)→1218 (June 21)→143 (September 25). The blood IL-3 andGM-CSF levels both showed low values before and after IFN-γ treatment.On the other hand, blood IL-5 and IL-4 were decreased followingtreatment; IL-5 was 18.5 pg/ml before treatment, and 5.0 pg/ml or lessafter treatment, and IL-4 was 15.6 pg/ml before treatment, and 4.6 pg/mlafter treatment. TABLE 2 Day of examination June 17 June 21 Erythemas 10 Blister 1 0 Erosions 1 0

[Clinical Case 3] Example (3) of Treatment with IFN-γ in BP Patient

-   Subject: A 67-year-old female.-   Chief complaints: Systemic edematous erythemas, blister and    erosions.-   Family history: Nothing of note.-   Past history: Nothing particular to mention.-   Present illness and course: IFN-γ, 2,000,000 JRU (1V), was    administered by i.v. drip infusion on August 26, but urinary tract    infection was identified, thus requiring its discontinuation. Then,    IFN-γ, 2,000,000 JRU (1V), was administered once daily by i.v. drip    infusion consecutively from September 10 to September 16.

Before IFN-γ treatment (August 26), erythemas, blister and erosionsdeveloped systemically at multiple sites (FIG. 3 a). After treatment(September 17), the symptoms were considerably relieved, and no blisterdeveloped newly (FIG. 3 b). Currently, all the affected sites show onlypigmentations, and none of erythemas, blister and erosions are observed.The evaluations were 2 (September 13)→1 (September 17) for erythemas, 2(September 13)→0 (September 17) for blister, and 2 (September 13)→1(September 17) for erosions, as shown in Table 3.

The peripheral blood eosinophil count decreased as follows: 288 (August26)→310 (September 2)→39 (September 13)→0 (September 17). The bloodIL-3, IL-5 and GM-CSF levels all showed low values before and afterIFN-γ treatment (August 26, September 17). On the other hand, blood IL-4was slightly decreased: 16.8 pg/ml before treatment (August 26), and12.7 pg/ml after treatment (September 17). TABLE 3 Day of examinationSeptember 13 September 17 Erythemas 2 1 Blister 2 0 Erosions 2 1

[Clinical Case 4] Example (4) of Treatment with IFN-γ in BP Patient

-   Subject: A 68-year-old female.-   Chief complaints: Systemic edematous erythemas, blister and    erosions.-   Family history: Nothing of note.-   Past history: Nothing particular to mention.-   Present illness and course: IFN-γ, 2,000,000 JRU (1V), was    administered once daily consecutively from January 21 to January 27    by intravenous drip infusion.

Before IFN-γ treatment (January 21), erythemas, blister and erosionsdeveloped systemically at multiple sites. After treatment (January 28),the symptoms were considerably relieved, and no blister developed newly.After one week of treatment (February 5), only pigmentations wereobserved, and none of erythemas, bullae and erosions were observed. Theevaluations were 2 (January 24)→1 (January 28)→0 (February 5) forerythemas, 2 (January 24)→0 (January 28)→0 (February 5) for blister, and2 (January 24)→1 (January 28)→0 (February 5) for erosions, as shown inTable 4.

The peripheral blood eosinophil count decreased as follows: 5334(January 21)→5202 (January 24)→5251 (January 28)→2736 (January 31)→0(February 5). The blood IL-3, IL-4, and GM-CSF levels all showed lowvalues before and after IFN-γ treatment (January 21, January 28). On theother hand, blood IL-5 was decreased: 76.1 pg/ml before treatment(January 21), and 28.3 pg/ml after treatment (January 28). TABLE 4 Dayof examination January 24 January 28 February 5 Erythemas 2 1 0 Blister2 0 0 Erosions 2 1 0

[Clinical Case 5] Example (5) of Treatment with IFN-γ in BP Patient

-   Subject: A 93-year-old male.-   Chief complaints: Systemic edematous erythemas, blister and    erosions.-   Family history: Nothing of note.-   Past history: Diabetes, hypertension.-   Present illness and course: IFN-γ, 2,000,000 JRU (1V), was    administered once daily consecutively from June 6 to June 12 by    intravenous drip infusion.

Before IFN-γ treatment (June 6), erythemas, blister and erosionsdeveloped systemically at multiple sites. After treatment (June 12), thesymptoms were considerably relieved, and no blister developed newly.After one week of treatment (June 19), only pigmentations were observed,and none of erythemas, blister and erosions were observed. Theevaluations were 3 (June 9)→2 (June 12)→1 (June 19) for erythemas, 2(June 9)→0 (June 12)→0 (June 19) for blister, and 2 (June 9)→1 (June12)→0 (June 19) for erosions, as shown in Table 5.

The peripheral blood eosinophil count decreased as follows: 1080 (May29)→190 (June 6)→71 (June 9)→54 (June 12)→0 (June 19). The blood IL-3and GM-CSF levels all showed low values before and after IFN-γ treatment(June 6, June 12). On the other hand, blood IL-4 and- IL-5 weredecreased; IL-4 was 7.5 pg/ml before treatment (June 6), and 4.0 pg/mlafter treatment (June 12), and IL-5 was 7.5 pg/ml before treatment (June6), and less than 5.0 pg/ml after treatment (June 12). TABLE 5 Day ofexamination June 9 June 12 June 19 Erythemas 3 2 1 Blister 2 0 0Erosions 2 1 0

[Clinical Case 6] Example (6) of Treatment with IFN-γ in BP Patient

-   Subject: A 55-year-old male.-   Chief complaints: Systemic edematous erythemas, blister and    erosions.-   Family history: Nothing of note.-   Past history: Nothing particular to mention.-   Present illness and course: IFN-γ, 2,000,000 JRU (1V), was    administered once daily consecutively from August 26 to September 1    by intravenous drip infusion.

Before IFN-γ treatment (August 26), erythemas, blister and erosionsdeveloped systemically at multiple sites (FIG. 4 a, FIG. 5 a). Aftertreatment (September 1), the symptoms were considerably relieved, and noblister developed newly (FIG. 4 b, FIG. 4 c, FIG. 5 c). After 10 days oftreatment (September 11), only pigmentations were observed, and none oferythemas, blister and erosions were observed. The evaluations were 3(August 28)→1 (September 1)→0 (September 11) for erythemas, 2 (August28)→0 (September 1)→0 (September 11) for blister, and 2 (August 28)→1(September 1)→0 (September 11) for erosions, as shown in Table 6.

The peripheral blood eosinophil count decreased as follows: 481 (August26)→148 (August 28)→192 (September 1)→86 (September 5)→0 (September 11).The blood IL-3, IL-5 and GM-CSF levels all showed low values before andafter IFN-γ treatment (August 26, September 1). On the other hand, bloodIL-4 was decreased; 24.8 pg/ml before treatment (August 26), and 17.2pg/ml after treatment (September 1). TABLE 6 Day of examination August28 September 1 September 11 Erythemas 3 1 0 Blister 2 0 0 Erosions 2 1 0

EFFECT OF THE INVENTION

The above results show that IFN-γ was excellently effective againstpemphigoid, an intractable disease, in all cases. Following IFN-γtreatment, the eosinophil count was clearly decreased simultaneouslywith the alleviation of clinical symptoms. IFN-γ was thus considered tosuppress Th2 cells, thereby suppressing the chemotaxis and function ofeosinophils and ameliorating the symptoms. According to similarconcepts, IFN-γ was reported to be administered in skin diseases,including eosinophilic pustular folliculitis (EPF)⁵⁾ and atopicdermatitis (AD)⁶⁾. In EPF, however, other drugs produce a markedresponse without presenting such clinical symptoms as to affect generalcondition. In AD, IFN-γ is slightly effective in an acute phase, butoften fails to take effect in a chronic phase. In the case ofpemphigoid, the elderly are affected most frequently, and theprogression of symptoms may exert influence on the general condition.Moreover, treatment extends over a long period, and side effects oftendevelop. The present invention has made it possible to provide a methodof treatment for pemphigoid for which there have been no fast-actingsafe therapies.

REFERENCES

-   1) Takekuni NAKAMA, Shingo TSUDA, et al.: Immunohistochemical study    of eosinophils using mouse anti-human ECP monoclonal antibodies    (EG2). J. of Clin. & Experimental Medicine 150:231-232, 1989.-   2) Takekuni NAKAMA, Shingo TSUDA: Ultrastructural and    immunocytechemical aspects of infiltrated eosinophils in bullous    pemphigoid. Electron Microscopy in Dermatology:181-185, 1994.-   3) Shingo TSUDA, Minoru MIYASATO, et al.: Eosinophil phenotypes in    bullous pemphigoid. Journal of Dermatology 19:270-279, 1992.-   4) Shingo TSUDA, Minoru MIYASATO, Takekuni NAKAMA, et al.: Skin    disease and eosinophils II. Hydroa. Eosinophilic infiltration and    its surroundings in skin: 151-176, J. Clin. Therapeutics &    Medicines, 1990.-   5) M Fushimi, Y Tokura, et al.: Eosinophilic pustular folliculitis    effectively treated with recombinant interferon-γ: suppression of    mRNA expression of interleukin 5 in peripheral blood mononuclear    cells. Br. J. Dermatology 134:766-772, 1996.-   6) Seth R. Stevens, MD; Jon M. Hanifin, et al.: Long-term    Effectiveness and Safety of Recombinant Human Interferon Gamma    Therapy for Atopic Dermatitis Despite Unchanged Serum IgE Levels.    Arch. Dermatol. 134:799-804, 1998.

1. An agent for treatment of pemphigoid, comprising interferon-γ as anactive ingredient.
 2. The agent for treatment according to claim 1, in aform suitable for administration in a daily dose of 200,000 to 4,000,000JRU.
 3. The agent for treatment according to claim 1, which is in a formsuitable for intravenous injection.
 4. The agent for treatment accordingto claim 1, further comprising an antihistaminic, an antiallergic and/ora corticosteroid.
 5. The agent for treatment according to claim 1,wherein pemphigoid is bullous pemphigoid, cicatricial pemphigoid, ornodular pemphigoid.
 6. The agent for treatment according to claim 1,wherein pemphigoid is bullous pemphigoid.
 7. The agent for treatmentaccording to claim 2, wherein said daily dose is, 2.000,000 JRU.
 8. Theagent for treatment according to claim 1, wherein said interferon-γ isan interferon-γ mutant.
 9. A therapeutic composition comprisinginterferon-γ as an active ingredient and a pharmaceutically acceptablecarrier, said interferon-γ being present in an amount effective to treatpemphigoid.
 10. A method for treating pemphigoid comprisingadministering to a patient the therapeutic composition of claim
 9. 11.The method according to claim 10 comprising administering saidcomposition intravenously.